Phenethylamine compounds

ABSTRACT

Substituted phenethylamines of formula (I) useful for treating phosphodiesterase IV related ##STR1## disease states are disclosed herein.

This application is a 371 of PCT/US94/09308 filed Aug. 19, 1994.

FIELD OF THE INVENTION

This invention relates to certain phenethylamines which are useful fortreating diseases where antagonizing the enzyme phosphodiesterase IVwill have a salutory effect.

BACKGROUND OF THE INVENTION

Bronchial asthma is a complex, multifactorial disease characterized byreversible narrowing of the airway and hyper-reactivity of therespiratory tract to external stimuli.

It is now understood that the symptoms of chronic asthma are themanifestations of three distinct processes: 1) an early response toantigen, 2) a delayed or late response to antigen, and 3) chronicinflammation and airway hyper-reactivity. Cockcroft, Ann. Allergy55:857-862, 1985; Larsen, Hosp. Practice 22:113-127, 1987. The agentscurrently available (β-adrenoceptor agonists, steroids, methylxanthines,disodium cromoglycate) are inadequate to control the disease; none ofthem modify all three phases of asthma and nearly all are saddled withlimiting side effects. Most importantly, none of the agents, with thepossible exception of steroids, alter the course of progression ofchronic asthma.

Identification of novel therapeutic agents for asthma is made difficultby the fact that multiple mediators are responsible for the developmentof disease. Thus, it seems unlikely that eliminating the effects of asingle mediator will have a substantial effect on all three componentsof chronic asthma. An alternative to the "mediator approach" is toregulate the activity of the cells responsible for the pathophysiologyof the disease.

Cyclic AMP modulates the activity of most, if not all, of the cells thatcontribute to the pathophysiology of extrinsic (allergic) asthma. Assuch, an elevation of cAMP would produce beneficial effectsincluding: 1) airway smooth muscle relaxation, 2) inhibition of mastcell mediator release, 3) suppression of neutrophil degranulation, 4)inhibition of basophil degranulation, and 5) inhibition of monocyte andmacrophage activation. Hence, compounds that activate adenylate cyclaseor inhibit PDE should be effective in suppressing the inappropriateactivation of airway smooth muscle and a wide variety of inflammatorycells. The principal cellular mechanism for the inactivation of cAMP ishydrolysis of the 3'-phosphodiester bond by one or more of a family ofisozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotidephosphodiesterase (PDE) isozyme, PDE IV, is responsible for cyclic AMPbreakdown in airway smooth muscle and inflammatory cells. Torphy,"Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmaticAgents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd.(1989). Research indicates that inhibition of this enzyme not onlyproduces airway smooth muscle relaxation, but also suppressesdegranulation of mast cells, basophils and neutrophils along withinhibiting the activation of monocytes and neutrophils. Moreover, thebeneficial effects of PDE IV inhibitors are markedly potentiated whenadenylate cyclase activity of target cells is elevated by appropriatehormones or autocoids, as would be the case in vivo. Thus PDE IVinhibitors would be effective in the asthmatic lung, where levels ofprostaglandin E₂ and prostacyclin (activators of adenylate cyclase) areelevated. Such compounds would offer a unique approach toward thepharmacotherapy of bronchial asthma and possess significant therapeuticadvantages over agents currently on the market.

The compounds of this invention also inhibit production of TumorNecrosis Factor (TNF), a serum glycoprotein. Excessive or unregulatedTNF production is implicated in mediating or exacerbating a number ofdiseases including rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions; sepsis,septic shock, endotoxic shock, gram negative sepsis, toxic shocksyndrome, adult respiratory distress syndrome, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sacroidosis, boneresorption diseases, reperfusion injury, graft vs. host reaction,allograft rejections, fever and myalgias due to infection, such asinfluenza, cachexia secondary to infection or malignancy, cachexiasecondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDSrelated complex), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis, or pyresis.

TNF has been implicated in various roles with the human acquired immunedeficiency syndrome (AIDS). AIDS results from the infection of Tlymphocytes with Human Immunodeficiency Virus (HIV). It has now beendiscovered that monokines, specifically TNF, are implicated in theinfection of T lymphocytes with HIV by playing a role in maintaining Tlymphocyte activation. Furthermore, once an activated T lymphocyte isinfected with HIV, the T lymphocyte must continue to be maintained in anactivated state to permit HIV gene expression and/or HIV replication. Ithas also been discovered that monokines, specifically TNF, areimplicated in activated T cell-mediated HIV protein expression and/orvirus replication by playing a role in maintaining T lymphocyteactivation. Therefore, interference with monokine activity such as byinhibition of monokine production, notably TNF, in an HIV-infectedindividual aids in limiting the maintenance of T cell activation,thereby reducing the progression of HIV infectivity to previouslyuninfected cells which results in a slowing or elimination of theprogression of immune dysfunction caused by HIV infection. Monocytes,macrophages, and related cells, such as kupffer and glial cells, havealso been implicated in maintenance of the HIV infection. These cells,like T cells, are targets for viral replication and the level of viralreplication is dependent upon the activation state of the cells. SeeRosenberg et al., The Immunopatho-genesis of HIV Infection, Advances inImmunology, Vol. 57, (1989)!. Monokines, such as TNF, have been shown toactivate HIV replication in monocytes and/or macrophages See. Poli, etal., Proc. Natl. Acad. Sci., 87:782-784 (1990)!, therefore, inhibitionof monokine production or activity aids in limiting HIV progression asstated above for T cells.

It has now been discovered that monokines are implicated in certaindisease-associated problems such as cachexia and muscle degeneration.Therefore, interference with monokine activity, such as by inhibition ofTNF production, in an HIV-infected individual aids in enhancing thequality of life of HIV-infected patients by reducing the severity ofmonokine-mediated disease associated problems such as cachexia andmuscle degeneration.

TNF is also associated with yeast and fungal infections. SpecificallyCandida Albicans has been shown to induce TNF production in vitro inhuman monocytes and natural killer cells. See Riipi et al., Infectionand Immunity, Vol. 58, No. 9, p. 2750-54 (1990); and Jafari et al.,Journal of Infections Diseases, Vol. 164, p. 389-95 (1991). See alsoWasan et al., Antimicrobial Agents and Chemotherapy, Vol. 35, No. 10, p.2046-48 (1991) and Luke et al., Journal of Infectious Diseases, Vol.162, p. 211-214 (1990)!.

The discovery of a class of compounds which inhibit the production ofTNF will provide a therapeutic approach for the diseases in whichexcessive, or unregulated TNF production is implicated. That is providedherewith.

SUMMARY OF THE INVENTION

In a first aspect, this invention covers a compound of formula I##STR2## or a salt thereof, where Q is a radical of formula A, B, C or D##STR3##

R₁ is lower alkyl substituted by 1 or more halogens, aryl, halosubstituted aryl, aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl,indanyl, indenyl, C₇₋₁₁ polycycloalkyl, tetrahydrofuryl, furyl,tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl,tetrahydrothiopyranyl, thiopyranyl, --CR₄ R₅ -C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl, or a C₄₋₆ cycloalkenyl containing one or two unsaturatedbonds, wherein the cycloalkyl and heterocyclyl moieties unsubstituted orsubstituted by 1 to 3 methyl groups or one ethyl group;

R₂ is --CH₃ or --CH₂ CH₃ unsubstituted or substituted by 1 or morehalogens;

R₃ is lower alkyl unsubstituted or substituted by one or more halogens,--CR₄ R₅ OR₄, --CR₄ R₅ NR₄ R₉, --CR₄ (OR₄)CR₄ R₅ OR₄,2,2-dimethyl-1,3-dioxolan-4-yl, --NR₉ C(O)NR₄ R₉, --NR₄ R₉, --S(CR₄R₅)_(n) CH₃ where n is 0-5, or --P(O)(OR₁₂)₂ ;

R₄ and R₅ are independently hydrogen, methyl or ethyl;

R₆ is hydrogen, halogen, --C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl,--CH₂ NHC(O)C(O)NH₂, --CH--CR₄ R₅, cyclopropyl unsubstituted orsubstituted by R₄, --CN, --OR₄, --CH₂ OR₄, --NR₄ R₅, --CH₂ NR₄ R₅,--C(O)R₄, --C(O)OR₄, --C(O)NR₄ R₅, or --C.tbd.CR₄ ; provided that whenR₆ is OH, then R₇ is hydrogen or --CH₃ unsubstituted or substituted by 1to 3 fluoro groups;

R₇ is hydrogen, F, --CN, or --CH₃ unsubstituted or substituted by 1 to 3fluoro groups, or R₆ and R₇ together can form a keto (═O) moiety;

R₈ is H, F, CN, C₁₋₂ alkyl optionally substituted by 1 or more fluorogroups, C(O)NR₄ R₅, or C(O)OR₄ ;

R₉ is H, --OR₁₁, unsubstituted or substituted --(CH₂)_(m) Ar where m is0-2, or unsubstituted or substituted C₁₋₆ alkyl, wherein optionalsubstituents comprise from one to three groups independently selectedfrom the group consisting of --CH₃ or --CH₂ CH₃ unsubstituted orsubstituted by 1 or more halogens, --NO₂, --Si(R₄)₃, --NR₁₀ R₁₁,--C(O)R₄, --C(O)OR₄, --OR₄, --CN, --C(O)NR₁₀ R₁₁, --OC(O)NR₁₀ R₁₁,--OC(O)R₁₂, --NR₁₀ C(O)NR₁₀ R₁₁, --NR₁₀ C(O)R₁₁, --NR₁₀ C(O)OR₁₂, --NR₁₀C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀ R₁₁, --C(NCN)SR₉, --NR₁₀C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁, --NR₁₀ S(O)₂ R₁₂, --S(O)_(m') R₁₂where m' is 0-2, --NR₁₀ C(O)C(O)NR₁₀ R₁₁, --NR₁₀ C(O)C(O)R₁₀, thiazolyl,imidazolyl, oxazolyl, pyrazolyl, triazolyl, and tetrazolyl;

R₁₀ is --OR₁₁ or --R₁₁ ;

R₁₁ is hydrogen, or --C₁₋₄ alkyl unsubstituted or substituted by one tothree fluoro groups; or when R₁₀ and R₁₁ are comprise part of the group--NR₁₀ R₁₁ they may together with the nitrogen form a 5 to 7 memberedring which may contain at least one additional heteroatom which is O, N,or S;

R₁₂ is --C₁₋₄ alkyl unsubstituted or substituted by one to three fluorogroups;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, wherein each of these heterocyclic ringsis connected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups;

R₁₄ is OH or OR₁₂ ;

R₁₅ is unsubstituted or substituted --(CH₂)_(m) Ar where m is 0-2, orunsubstituted or substituted C₁₋₆ alkyl, wherein optional substituentscomprise from one to three groups independently selected from the groupconsisting of --CH₃ or --CH₂ CH₃ unsubstituted or substituted by 1 ormore halogens, --NO₂, --Si(R₄)₃, --NR₁₀ R₁₁, --C(O)R₄, --C(O)OR₄, --OR₄,--CN, --C(O)NR₁₀ R₁₁, --OC(O)NR₁₀ R₁₁, --OC(O)R₁₂, --NR₁₀ C(O)NR₁₀ R₁₁,--NR₁₀ C(O)R₁₁, --NR₁₀ C(O)OR₁₂, --NR₁₀ C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁,--C(NCN)NR₁₀ R₁₁, --C(NCN)SR₉, --NR₁₀ C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁,--NR₁₀ S(O)₂ R₁₂, --S(O)_(m') R₁₂ where m' is 0-2, --NR₁₀ C(O)C(O)NR₁₀R₁₁, --NR₁₀ C(O)C(O)R₁₀, thiazolyl, imidazolyl, oxazolyl, pyrazolyl,triazolyl, and tetrazolyl;

Ar is 2-, 3- or 4-pyridyl, pyrimidyl, pyridazyl, 2-imidazolyl,morpholino, or phenyl;

X₁ is YR₂, halogen, nitro, --NR₄ R₅, or formyl amine;

X₂ is O or NR₄ ;

X₃ is hydrogen or X₁ ;

Y is O, S, SO or SO₂ ;

Z is O or NCN;

provided that

a) Z is NCN only when R₃ is --NR₄ R₅ or --S(CR₄ R₅)_(n) CH₃ ; or

b) when X₁ is --NR₄ R₅ or formyl amine, then R₁ is not CH₃ or C₂ H₅ whenX₂ is O and X₃ is H or halogen; or

c) when R₃ is CR₄ R₅ NR₄ R₉, and X₂ is O, and R₁ is phenyl, then one ofR₆, R₇, or R₈ is other than H; or

d) when Z is NCN, and X₁ is YR₂, and Y is O, and R₂ is CH₃ and R₃ isNH₂, and R₉ is H, OH, OCH₃ or CH₃, and R₈ is H and R₆ and R₇ are bothhydrogen, or are hydrogen and methyl, hydrogen and CF₃ or hydrogen andethyl, and X₂ is O, then R₁ is not CF₃, CF₂ H, or CF₂ CF₂ H; or

e) when Z is NCN, and X is YR₂, and Y is O, and R₂ is CH₃ and R₃ is NH₂,and R₉ is H, OH OCH₃ or CH₃, and R₈ is H, and R₆ and R₇ are bothhydrogen, or are hydrogen and methyl, hydrogen and CF₃ or hydrogen andethyl, and X₂ is NR₄ and R₄ is CH₃, then R₁ is not CH₃ ; or

f) when Q is A, and X₂ is O, R₁ is aryl or halo-substituted aryl, R₆ ishalo or OR₄, R₇ is H, R₈ is CH₃ or CH₂ F and R₉ is H or C₁₋₃ alkyl, thenR₁₅ is not lower alkyl, mono or dichlorosubstituted lower alkyl, orunsubstituted or subsitituted phenyl; or

g) when Q is B, and X₂ is O, R₁ is aryl or halo-substituted aryl, R₇ isH, R₈ is CH₃ or CH₂ F; R₉ is H or C₁₋₃ alkyl, then R₆ is other than haloor OR₄.

These compounds are useful in the mediation or inhibition of theenzymatic activity (or catalytic activity) of phosphodiesterase IV (PDEIV). The novel compounds of the Formula (I) also have Tumor NecrosisFactor (TNF) inhibitory activity.

This invention also relates to a composition, including a pharmaceuticalcomposition, comprising a compound of the Formula I and a carrier ordiluent.

The invention also relates to a method of mediation or inhibition of theenzymatic activity (or catalytic activity) of phosphodiesterase IV,including mammals which comprises administering to a mammal in needthereof an effective amount of a compound of Formula I.

The invention further provides a method for treating allergic andinflammatory diseases which comprises administering to a mammal,including humans, in need thereof, an effective amount of a compound ofthe Formula I.

The invention also provides a method for treating asthma which comprisesadministering to a mammal, including humans, in need thereof aneffective amount of a compound of the Formula I.

This invention also relates to a method of inhibiting TNF production ina mammal, including humans, which method comprises administering to amammal in need of such treatment an effective TNF inhibiting amount of acompound of the Formula (I). This method may be used for theprophylactic treatment or prevention of certain TNF mediated diseasestates amenable thereto.

This invention also relates to a method of treating a human afflictedwith a human immunodeficiency virus (HIV), which comprises administeringto such human an effective TNF inhibiting amount of a compound of theFormula (I).

The compounds of the Formula (I) are also useful in the treatment ofadditional viral infections, where such viruses are sensitive toupregulation by TNF or will elicit TNF production in vivo.

In yet a further aspect, this invention covers a process for making acompound of formula I, which process comprises one or more of thefollowing steps:

a) forming a salt;

b) treating an amine with a lower alkyl acylating agent to form thecorresponding amide;

c) treating an amine with biuret to form the correspondingimidodicarbamide;

d) hydrolyzing the product of an amine treated with trimethylsilylisocyanate to form the corresponding urea;

e) treating an amine with cyanodithioiminiocarbonate to form thecorresponding N² -cyano-S-methyl-N¹ -isothiouriedo;

f) treating an N² -cyano-S-methyl-N¹ -isothiouriedo with an amine toform the corresponding N'-cyanocarboximidamide;

g) treating a amine with a mixture comprising(4S)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid and isobutylchloroformate in the presence of an organic base to form thecorresponding 2,3-dihydroxypropanamide and the corresponding carbamate;

h) treating an amine with 4(R)-2,2-dimethyl-1,3-dioxaolane-4-carboxylicacid to form the corresponding 2,2-dimethyl-1,3-dioxolane-4-carboxamide;

i) treating an amine with trimethyl phosphonoformate to form thecorresponding phosphonoformamide;

j) reacting an amine with dimethoxyformylphosphonyl chloride;

k) treating an aminopropionitrile with acetoacetyl chloride to form thecorresponding 2-acetoxyacetamide;

l) hydrolyzing a protected aminoacetamide to form the corresponding2-aminoacetamide; or

m) treating an amine with a sulfonylating agent to form thecorresponding sulfonamide.

SPECIFIC EMBODIMENTS

Specific embodiments of this invention are defined and illustratedbelow.

The following terms and phrases used herein are to be interpreted ashaving the meaning or meanings given hereafter. "Lower alkyl" means agroup having 1 to 6 carbon atoms. This included normal, secondary andtertiary form where such forms can exist, e.g., isopropyl, t-butyl andthe like. Normal, or linear, radicals are preferred, especially methyl,ethyl, propyl, butyl, pentyl and hexyl. Halo means fluoro, chloro, bromoand iodo. The term "cycloalkyl" or "cycloalkyl alkyl" as used herein ismeant to include those rings of 3-7 carbon atoms, such as cyclopropyl,cyclopropylmethyl, cyclopentyl or cyclohexyl. "Aryl", unless specifiedotherwise, means an aromatic ring or ring system of 6-10 carbon atomssuch as phenyl. Preferably the aryl is monocyclic, i.e., phenyl. Thealkyl chain is meant to include both straight or branched chain radicalsof 1 to 4 carbon atoms.

Some compounds of formula I may be sufficiently basic so as form acidaddition salts. This work includes all such salts, particularly thosewhich retain the activity of the parent base and are acceptable forpharmaceutical use. Making acid addition salts is a well know art andany documented procedure is expected to provide the desired product inthe context of this invention.

"Inhibiting the production of TNF" means,

a) a decrease of excessive in vivo TNF levels in a human to normallevels or below normal levels by inhibition of the in vivo release ofTNF by all cells, including but not limited to monocytes or macrophages;

b) a down regulation, at the translational or transcription level, ofexcessive in vivo TNF levels in a human to normal levels or below normallevels; or

c) a down regulation, by inhibition of the direct synthesis TNF as apostrunslational event.

"TNF mediated disease states" means all disease states in which TNFplays a role, either by production of TNF itself, or by TNF causinganother cytokine to be released, such as but not limited to IL-1, orIL-6. A disease state in which IL-1, for instance is a major component,and whose production or action is exacerbated or which is secreted inresponse to TNF, would therefore be considered a disease state mediatedby TNF.

"Cytokine" means any secreted polypeptide that affects the functions ofother cells, and is a molecule which modulates interactions betweencells in the immune or inflammatory response. A cytokine includes, butis not limited to monokines and lymphokines regardless of which cellsproduce them. For instance, a monokine is generally referred to as beingproduced and secreted by a mononuclear cell, such as a macrophage and/ormonocyte but many other cells produce monokines, such as natural killercells, fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes, andβ-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines for the present inventioninclude, but are not limited to Interleukin-1 (IL-1), Interleukin-6(IL-6), Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factorbeta (TNFβ). Some compounds of formula I may exist in two distinctenantiomeric forms. Some compounds of Formula I may exist in at leasttwo distinct diasteriomeric forms possessing distinct physical andbiological properties. Furthermore some compounds of Formula I may existin a tautomeric form, such as the enol or enamine. All these forms arewithin the scope of this invention.

Preferred R₁ groups are cyclopropylmethyl, cyclopentymethyl,cyclohexylmethyl, cyclobutyl, cyclopentyl, cyclohexyl,tetrahydrofur-2-yl, cyclopentenyl, benzyl, or lower alkyl optionallysubstituted by 1 or more fluoro groups. When R₁ is lower alkylsubstituted by 1 or more halogens, the halogens are preferably fluorineand chlorine, more preferably a C₁₋₄ alkyl substituted by 1 or morefluoro groups, more preferably 1 or more times by fluorine. The mostpreferred halo substituted chain length is one or two carbons, and mostpreferred are the moieties --CF₃, --CH₂ F, --CHF₂, --CF₂ CHF₂, --CH₂CF₃, and --CH₂ CHF₂. Preferred R₁ substitutents are cyclopentyl,cyclopropylmethyl, --CF₃, and --CHF₂.

When R₁ is a C₇₋₁₁ polycycloalkyl, examples are bicyclo 2.2.1!-heptyl,bicyclo 2.2.2!octyl, bicyclo 3.2.1!octyl, tricyclo 5.2.1.0²,6 !decyl,additional examples of which are described in Saccamano et al., WO87/06576, published 5 Nov. 1987 which is incorporated herein byreference in its entirety.

Oxygen is the preferred X₂ radical.

As for X₁, the preferred radical is YR₂ where Y is oxygen. The preferredR₂ group is a methyl or ethyl unsubstituted or substituted by 1 or morehalogens. The preferred halogens are fluoro and chloro, most preferablyfluoro. The more preferred R₂ groups are methyl, --CF₃, --CHF₂, or --CH₂CHF₂ moiety. Most preferred are difluoromethyl and methyl.

Hydrogen is the referred X₃ radical.

As regards the Q group, the preferred radicals are those which form anamide, sulfonamide, imidodicarbamide, urea, N² -cyano-S-methyl-N¹-isothiouriedo, 2,3-dihydroxypropanamide,2,2-dimethyl-1,3-dioxolane-4-carboxamide, 2-acetoxyacetamide, or a2-aminoacetamide.

Preferred R₆ moieties are H, C(O)NH₂, C.tbd.CR₄, CN, C(O)H, CH₂ OH, CH₂F, CF₂ H, and CF₃. More preferred are C.tbd.CH and CN. R₇ is preferablyH or CN. R₈ is preferably H, --C(O)NH₂ or CN.

Preferred R₉ moieties include hydrogen, optionally substituted--(CH₂)₀₋₂ (2-, 3- or 4-pyridyl), (CH₂)₁₋₂ (2-imidazolyl), (CH₂)₂(4-morpholinyl), (CH₂)₂ (4-piperazinyl), (CH₂)₁₋₂ (2-thienyl), (CH₂)₁₋₂(4-thiazolyl), and (CH₂)₀₋₂ phenyl.

Preferred rings when R₁₀ and R₁₁ in the moiety --NR₁₀ R₁₁ together withthe nitrogen to which they are attached form a 5 to 7 membered ringoptionally containing at least one additional heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl,2-(R₈)-1-imidazolyl, 1-pyrazolyl, 3-(R₈)-1-pyrazolyl, 1-triazolyl,2-triazolyl, 5-(R₈)-1-triazolyl, 5-(R₈)-2-triazolyl,5-(R₈)-1-tetrazolyl, 5-(R₈)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl,morpholinyl, piperazinyl, 4-(R₈)-1-piperazinyl, or pyrrolyl ring.

Preferred R₁₅ moieties include, optionally substituted C₁₋₃ alkyl,--(CH₂)₀₋₂ (2-, 3-or 4-pyridyl), (CH₂)₁₋₂ (2-imidazolyl), (CH₂)₂(4-morpholinyl), (CH₂)₂ (4-piperazinyl), (CH₂)₁₋₂ (2-thienyl), (CH₂)₁₋₂(4-thiazolyl), and (CH₂)₀₋₂ phenyl.

Preferred rings for R₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4or 5-triazolyl 1,2,3!), (3- or 5-triazolyl 1,2,4!),(5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl 1,2,4!), (2-oxadiazolyl 1,3,4!), (2-thiadiazolyl 1,3,4!),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

Preferred are those compounds of formula (I) wherein R₁ is --CH₂-cyclopropyl, --CH₂ --C₅₋₆ cycloalkyl, --C₄₋₆ cycloalkyl,tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl, and --C₁₋₂ alkyloptionally substituted by 1 or more fluorines; R₂ is methyl orfluoro-substituted alkyl; R₆ is CN or C.tbd.CR₄ ; and X is YR₂.

Most preferred are those compounds wherein R₁ is --CH₂ -cyclopropyl,cyclopentyl, or CF₂ H; R₆ is CN or C.tbd.CH; X is YR₂ ; Y is oxygen; X₂is oxygen; X₃ is hydrogen; and R₂ is CF₂ H or methyl.

Phosphodiesterase IV inhibitors are useful in the treatment of a varietyof allergic and inflammatory diseases including: asthma, chronicbronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergicconjunctivitis, vernal conjunctivitis, eosinophilic granuloma,psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis,inflammatory bowel disease states including Crohn's disease, reperfusioninjury of the myocardium and brain, chronic glomerulonephritis,endotoxic shock and adult respiratory distress syndrome. In addition,PDE IV inhibitors are useful in treating diabetes insipidus, (KidneyInt. 37:362, 1990; Kidney Int. 35:494, 1989) and central nervous systemdisorders such as depression and multi-infarct dementia.

Compounds of Formula I are useful in treating, prophylactically ortherapeutically, disease states in humans which are exacerbated orcaused by excessive or unregulated TNF production. Therefore, thepresent invention also provides a method for inhibiting the productionof tumor necrosis factor (TNF) in an animal in need thereof, includinghumans, which method comprises administering to said animal an effectiveamount of a compound of formula I alone or mixed with a carrier.

Compounds of the Formula I may be administered systemically, topically,parenterally or by inhalation in conventional dosage forms prepared bycombining such agent with standard carriers according to conventionalprocedures in an mount sufficient to produce the desired therapeuticactivity for treatment of a TNF-mediated disease state or for use as aPDE IV inhibitor.

The daily dosage regimen, based on oral administration, is suitablyabout 0.001 mg/kg to 100 mg/kg, preferably 0.01 mg/Kg to 40 mg/Kg, of acompound of the Formula I or a pharmaceutically acceptable salt thereofcalculated as the free base. The active ingredient may be administeredfrom 1 to 6 times a day, sufficient to exhibit activity. Other doseageregimens may require more or less compound depending on the route bywhich they are administered, by the enchancing or retarding affects ofexcipients, to name two factors which can influence the dosage regimen.But optimizing a dosage regimen is within the scope of a person skilledin the art and can be determined by following well establishedtechniques for determining what may constitute an effective amount tocompound in a given situation.

The mount of a compound of the formula I required for therapeutic effecton topical administration will, of course, vary with the compoundchosen, the nature and severity of the condition and the animalundergoing treatment, and is ultimately at the discretion of the onedirecting the use of these compounds.

While it is possible for an active ingredient to be administered aloneas the raw chemical, it is preferable to present it via a vehicle ofsome sort. Appropriate forms for using these compounds may be preparedby conventional techniques. For pharmaceutical or veterinary use, acomposition of the present invention will comprising an effective,non-toxic amount of a compound of the formula I and a pharmaceuticallyacceptable carrier or diluent. The carrier(s) must be `acceptable` inthe sense of being compatible with the other ingredients of theformulation and not deleterious in the intended use. Preferably thecomposition is in unit dosage form, for example a tablet, capsule ormetered aerosol dose, so that the patient may self-administer a singledose.

By systemic administration is meant oral, intravenous, intraperitoneal,topical, inhalation and intramuscular administration. By topicaladministration is meant non-systemic administration and includes theapplication of a compound externally to the epidermis, to the buccalcavity and instillation of such a compound into the ear, eye and nose,and where the compound does not significantly enter the blood stream.The term `parenteral` as used herein includes intravenous,intramuscular, subcutaneous intranasal, intrarectal, intravaginal orintraperitoneal administration. The subcutaneous and intramuscular formsof parenteral administration are generally preferred.

For oral administration each dosage unit may contains from 1 mg to 100mg, and preferably from 10 mg to 30 mg of a compound of the formula I ora pharmaceutically acceptable salt thereof calculated as the free base.Appropriate dosage forms for inhalation include an aerosol formulationor a metered dose inhaler. The daily dosage regimen for a compound ofthe Formula (I) for intranasal administration and oral inhalation issuitably about 10 to about 1200 mg. As for topical use, a suitable doseof a TNF production inhibiting compound of the formula I is from about0.01 mg to about 100 mg of base for topical administration, the mostpreferred dosage being about 0.01 mg to about 30 mg, for example, 0.003mg to 10 mg administered two or three times daily. Formulations suitablefor topical administration include liquid or semi-liquid preparationssuitable for penetration through the skin to the site of inflammationsuch as liniments, lotions, creams, ointments or pastes, and dropssuitable for administration to the eye, ear or nose.

No unacceptable toxicological effects are expected when these compoundsare administered in accordance with the present invention.

SYNTHETIC METHODS

Compounds of Formula I can be prepared by one of skill in the artaccording to the procedures outlined in the Examples, infra. Thepreparation of any remaining compounds of the Formula I not describedtherein may be prepared by the analogous processes disclosed herein.

In general an amine is first prepared, that is a compound where R isNH₂, and then this intermediate is converted to the desired targetcompound by one or more steps, all of which are described below. Theseamines can be prepared by the methods set out in PCT/US91/04795; thoseprocesses and the amines disclosed there are incorporated herein byreference to the extent that information is necessary or useful forunderstanding how to make the amine precursors used in this work. By wayof illustration, a benzaldehyde of formula (a) ##STR4## is reacted withnitromethane in a suitable solvent such as acetic acid with a catalystat between about 80°-100° C. or using the conditions of Shales, et al.,J. Amer. Chem. Soc., 74, 4486 (1952) to provide the alkenylnitrate offormula (b). ##STR5##

Treating formula b with a reducing agent such as lithium aluminumanhydride or hydrogen with a heavy metal catalyst and an acid yields thecorresponding amine.

Alternatively, the aldehyde of formula a can be treated with a lithiumhalide and a silyl halide in an appropriate solvent followed by areducing agent, e.g., siloxane, providing a halide of formula (c)##STR6## where X₄ is the halogen derived from the lithium halide.Cyanide is then used to displace the halide. This nitrile is thenreduced, for example by hydrogen and suitable heavy metal catalyst suchas nickel with ammonia or palladium on carbon with an acid such asperchloric acid to obtain the primary amine.

Where R₆ is nitrile, such compounds can be prepared by dehydrating acompound of formula (d) ##STR7## using a reagent such as trifluoroaceticanhydride. This converts the amide to the nitrile and subsequently theBoc group is hydrolized, providing the primary amine. Alternativeprotecting groups can be used. See for example those disclosed inGreene, I., Protective Groups in Organic Synthesis, Wiley Publishers, NY(USA) (1981). Methods for making this compound are described inPCT/US91/04795, the publication noted above.

Converting the primary amines to compounds of formula I is illustratedin the Examples set out below. These chemistries, and analogousprocesses, will make all of the compounds of formula I.

ASSAY METHODS

The assay(s) used to confirm the PDE IV antagonistic activity of thesecompounds can be found in patent application PCT/US91/04795(International Publication No. WO 92/00968) published 23 Jan. 1992. Thatinformation is incorporate herein by reference. The compounds of formulaI have exhibited activity at levels consistent with those believed to beuseful in treating PDE IV related disease states in those assays.

The following Examples are given to illustrate how to make compounds offormula I and formulations and testing processes for confirming theiractivity. These are only examples and are not intended to limit theinvention in any fashion or with regards to its scope.

EXAMPLES Example 1 2-(3-Cyclopentyloxy-4-methoxyphenyl)ethylamine

1a. 3-Cyclopentyloxy-4-methoxybenzaldehyde A mixture of3-hydroxy-4-methoxybenzaldehyde (40 g, 0.26 mol), potassium carbonate(40 g, 0.29 mol) and bromocyelopentane (32 mL, 0.30 mol) indimethylformamide (0.25 L) was heated under an argon atmosphere at 100°C. After 4 h, additional bromocyclopentane (8 mL, 0.07 mol) was addedand heating was continued for 4 h. The mixture was allowed to cool andwas filtered. The filtrate was concentrated under reduced pressure andthe residue was partitioned between ether and aqueous sodium carbonate.The organic extract was washed with aqueous sodium carbonate and dried(potassium carbonate). The solvent was removed in vacuo and the residuewas purified by flash chromatography, eluting with 2:1 hexanes/ether, toprovide a pale yellow oil.

Analysis Calc. for C₁₃ H₁₆ O₃ : C 70.89, H 7.32; found: C 70.71, H 7.33.

1b. 3-Cyclopentyloxy-4-methoxy-β-nitrostyrene To a solution of3-cyclopentyloxy-4-methoxybenzaldehyde (6.04 g, 27.4 mmol) in glacialacetic acid (36 mL) under an argon atmosphere was added nitromethane(7.35 mL, 136.0 mmol) and ammonium acetate (3.15 g, 40.9 mmol). Theresulting mixture was heated at reflux for 3 h, then allowed to cool toroom temperature. The mixture was poured into water and extracted twicewith methylene chloride. The combined organic extracts were washedsuccessively with aqueous sodium bicarbonate and water and dried(potassium carbonate). Removal of the solvent in vacuo and purificationof the residue by flash chromatography, eluting with 1:1 methylenechloride/hexanes, provided the nitrostyrene as a bright yellow solid:m.p. 133°-134° C.

Analysis Calc. for C₁₄ H₁₇ NO₄ : C 63.87, H 6.51, N 5.32; found: C64.08, H 6.42, N 5.33.

1c. 2-(3-Cyclopentyloxy-4-methoxyphenyl)ethylamine. To a suspension oflithium aluminum hydride (10.8 g, 28.5 mmol) in ether (250 mL) at 0° C.under an argon atmosphere was added dropwise a solution of3-cyclopentyloxy-4-methoxy-β-nitrostyrene (15 g, 57.0 mmol) intetrahydrofuran (85 mL). The resulting mixture was allowed to warm toroom temperature and stirred overnight. The reaction mixture was cooledto 0° C. and quenched by the successive dropwise addition of water (11mL), 15% sodium hydroxide (11 mL) and water (33 mL). The mixture wasfiltered through a pad of Celite and the flu-ate was washed successivelywith water, 10% hydrochloric acid and water. The aqueous washes werecombined, made basic with saturated aqueous potassium carbonate andextracted three times with ether and twice with methylene chloride. Theorganic layers were combined and dried (potassium carbonate). Removal ofthe solvent in vacuo provided the amine. A portion of the crude aminewas purified by flash chromatography, eluting with 1:10:90water/methanol/chloroform.

Analysis Calc. for C₁₄ H₂₁ NO₂.5/8 H₂ O: C 68.19, H 9.09, N 5.68; found:C 68.39, H 9.16, N 5.85

Example 2 N- 2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!acetamide

To a solution of crude 2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine(0.5 g, 2.1 mmol) in pyridine (1.8 mL) under an argon atmosphere wasadded acetic anhydride (1.25 mL). The resulting solution was stirred atroom temperature for 16 h and then concentrated under reduced pressure.The residue was dissolved in methylene chloride, washed with water anddried (sodium sulfate). The solvent was removed in vacuo, the residuewas purified by flash chromatography, eluting with 4% methanol/ether,and then triturated with ether to provide the acetamide: m.p. 87°-88° C.

Analysis Calc. for C₁₆ H₂₃ NO₃ : C 69.29, H 8.36, N 5.05; found: C69.11, H 8.17, N 5.00.

Example 3 N-2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!methanesulfonamide

To a solution of crude 2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine(0.25 g, 1.1 mmol) in methylene chloride (2 mL) at 0° C. under an argonatmosphere was added triethylamine (0.2 mL, 1.43 mmol) andmethanesulfonyl chloride (0.106 mL, 1.37 mmol). The resulting solutionwas stirred at room temperature for 16 h, diluted with methylenechloride, washed with water and dried (magnesium sulfate). The solventwas removed in vacuo, the residue was purified twice by flashchromatography, eluting with 1:2 hexane/ether, to provide an oil.

MS (DCI, CH₄) m/e 313 (M⁺).

Example 4 Dimethyl N-2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!phosphonoformamide

A mixture of trimethyl phosphonoformate (0.27 mL, 2.0 mmol) and2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (0.47 g, 2.0 mmol) wasallowed to stand under an argon atmosphere for 3 h. During this time,the mixture was sonicated twice for 3 min. The mixture was dissolved inmethylene chloride and washed successively with 10% hydrochloric acidand water and dried (potassium carbonate). The solvent was removed invacuo and the residue was purified by two successive flashchromatographies, eluting first with 1.5:98.5 methanol/methylenechloride and subsequently with 75:25 ethyl acetate/hexanes, to providethe phosphonoformamide.

Analysis Calc. for C₁₇ H₂₆ NO₆ P.3/4 H₂ O: C 53.04, H 7.20, N 3.64, P8.05; found: C 52.94, H 6.92, N 3.61, P 8.15.

Example 5 N- 2-(3-Cyclopentyloxy-3-methoxyphenyl)ethyl!imidodicarbamide

A solution of 2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (0.24 g,1.0 mmol) and biuret (0.52 g, 5.0 mmol) in dimethylformamide (6 mL)under an argon atmosphere was heated to 110° C. for 3 h. The reactionmixture was allowed to cool to room temperature and was concentratedunder reduced pressure. The residue was partitioned between methylenechloride and water, and the organic extract was dried (magnesiumsulfate). The solvent was removed in vacuo and the residue was purifiedby flash chromatography, eluting first with 10% ethyl acetate/methylenechloride and then with 4% methanol/methylene chloride. An off-whitesolid was obtained, which was further purified by flash chromatography,eluting with 2.5% methanol/methylene chloride, to provide an off.

Analysis Calc. for C₁₆ H₂₃ N₃ O₄.1/2 H₂ O: C 58.16, H 7.32, N 12.69;found: C 58.34, H 7.12, N 12.72.

Example 6 Dimethyl N-2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamino!phosphonoformate

To phosphorus pentachloride (0.42 g, 2.0 mmol) was added trimethylphosphonoformate (0.27 mL, 2.0 mmol) and the resulting mixture wasstirred at room temperature under an argon atmosphere for 4 h. Themixture was concentrated under reduced pressure, dissolved intetrahydrofuran (2 mL) and added to a -78° C. solution containing2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (0.48 g, 2.0 mmol) anddiisopropylethylamine (0.39 mL, 2.2 mmol) in tetrahydrofuran (3 mL)under an argon atmosphere. The reaction mixture was stirred for 1.5 h at-78° C. and quenched by the addition of ammonium chloride. The solventwas removed under reduced pressure, and the residue was partitionedbetween dilute aqueous hydrochloric acid and methylene chloride. Theorganic extract was washed with water and dried (potassium carbonate).The solvent was removed in vacuo and the residue was purified by twosuccessive flash chromatographies, eluting first with 2.5:50:50methanol/methylene chloride/hexanes and subsequently with 15:85 ethylacetate/methylene chloride, to provide the phosphonoformate.

Analysis Calc. for C₁₇ H₂₆ NO₆ P.1/3 H₂ O: C 54.11, H 7.12, N 3.71, P8.21; found: C 54.21, H 7.20, N 3.82, P 8.24.

Example 7 N- 2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!urea

To a solution of 2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (0.47 g,2.0 mmol) in tetrahydrofuran (10 mL) under an argon atmosphere was addedtrimethylsilyl isocyanate (0.42 mL, 3.1 mmol). The resulting mixture washeated at reflux for 1 h, was allowed to cool to room temperature andthen was stirred overnight. The reaction mixture was again heated toreflux for an additional 5 h and allowed to cool to room temperature.Ammonium chloride was added, and the mixture was concentrated underreduced pressure. The residue was partitioned between methylene chlorideand water. The organic extract was washed successively with 10%.hydrochloric acid and water and dried (potassium carbonate). Removal ofthe solvent in vacuo and purification of the residue by flashchromatography, eluting with 3% methanol/methylene chloride, providedthe urea as a white solid: m.p. 136°-37° C. Analysis Calc. for C₁₅ H₂₂N₂ O₃ : C 64.73, H 7.97, N 10.06; found: C 64.66, H 7.97, N 10.28.

Example 8 1-(N² -Cyano-S-methyl-N¹-isothiouriedo)-2-(3-cyclopentyloxy-4-methoxyphenyl)ethane

To a solution of 2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (0.31 g,1.31 mmol) in dry pyridine (5 mL) under an argon atmosphere was addeddimethyl N-cyanodithioiminiocarbonate (0.37 g, 2.56 mmol). The resultingmixture was heated at reflux for 3 h, then allowed to cool to roomtemperature and concentrated under reduced pressure. The residue wasdissolved in methylene chloride and washed successively with diluteaqueous hydrochloric acid and water and dried (potassium carbonate). Thesolvent was removed in vacuo and the residue was purified by flashchromatography, eluting with 4:6 ethyl acetate/hexanes, to provide awhite solid: m.p. 112°-113° C.

Analysis Calc. for C₁₇ H₂₃ N₃ O₂ S.1/3 H₂ O: C 60.15, H 7.03, N 12.38, S9.44; found: C 60.02, H 6.93, N 12.55, S 9.26.

Example 9 N'-Cyano-1-2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!carboximidamide

A solution of 1-(N₂ -cyano-S-methyl-N¹-isothiouriedo-2-(3-cyclopentyloxy-4-methoxyphenyl)ethane (0.22 g, 0.67mmol) in tetrahydrofuran (4 mL) was added to a suspension of sodiumhydride (80% dispersion, 0.027 g, 0.9 mmol) in tetrahydrofuran (2.5 mL)at room temperature under an argon atmosphere. After 2 h, the mixturewas heated to 50° C. for 2 h, was cooled to room temperature, wastreated with di-t-butyldicarbonate (0.29 g, 1.34 mmol) and was allowedto stir at room temperature overnight. The mixture was quenched withammonium chloride, was diluted with methylene chloride, was washedsuccessively with dilute sodium bicarbonate, dilute hydrochloric acidand then was dried (potassium carbonate). The solvent was evaporated andthe residue was purified by flash chromatography, eluting with 15% ethylacetate/hexanes, to provide an oil (0.19 g, 69%). This oil was placed inliquid ammonia at -45° C., the mixture was stirred for 8 h and theammonia was allowed to evaporate overnight at room temperature. Theresidue was dissolved in methylene chloride (2 mL) at 0° C. under anargon atmosphere and treated with trifluoroacetic acic (0.5 mL). After45 min, solid sodium bicarbonate was added, the mixture was diluted withmethylene chloride, the organic layer was washed with 5% aqueous sodiumbicarbonate and then with water. The organic extract was dried(potassium carbonate) and evaporated. The residue was purified by flashchromatography, eluting with 3-20% isopropanol/methylene chloride, toprovide a solid: m.p. 53°-55° C.

Analysis Calc. for C₁₆ H₂₂ N₄ O₂.3/4 H₂ O: C 60.84, H 7.50, N. 17.74;found: C 60.70, H 7.07, N 17.35.

Example 10 N- 2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!acetamide

10a. N-(t-Butoxycarbonyl)-2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamineA solution of 2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (2.5 g,10.6 mmol) in methylene chloride (25 mL) was treated witht-butyloxycarbonylanhydride (2.5 mL, 11 mmol) and stirred under an argonatmosphere for 2 h. The solvent was removed in vacuo and the residue waspurified by flash chromatography, during with 1:1 ether/hexanes, toprovide a colorless oil.

10b.N-(t-Butoxycarbonyl)-2-(3-cyclopentyloxy-4-methoxyphenyl)-N-methylethylamineA solution ofN-(t-butoxycarbonyl)-2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (1.2g, 3.6 mmol) in dimethylformamide (10 mL) was treated with sodiumhydride (0.12 g of 80% dispersion, 4 mmol) and stirred at roomtemperature under an argon atmophere for 2 h. Methyl iodide (0.3 mL, 4.8mmol) was added and stirring was continued for another 3 h. The solventwas removed in vacuo and the residue was partitioned between methylenechloride and acidic water. The organic layer was dried (potassiumcarbonate) and evaporated. Purification by flash chromatography, elutingwith 3:1 hexanes/ether, provided an oil.

10c. 2-(3-cyclopentyloxy-4-methoxyphenyl)-N-methylethylamine A solutionofN-(t-butoxycarbonyl)-2-(3-cyclopentyloxy-4-methoxyphenyl)-N-methylethylamine(0.65 g, 1.86 mmol) in methylene chloride (5 mL) was treated withtrifluoroacetic acid (2 mL) and stirred under an argon atmosphere for 1h. The solvent was removed in vacuo and the residue was partitionedbetween methylene chloride and 5% sodium bicarbonate. The organic layerwas dried (potassium carbonate) and evaporated to an oil.

10 d. N- 2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!acetamide A solutionof 2-(3-cyclopentyloxy-4-methoxyphenyl)-N-methylethylamine (0.12 g, 0.48mmol) in pyridine (0.4 mL) and acetic anhydride (0.28 mL) was stirred atroom temperature under an argon atmosphere for 24 h. The liquids wereevaporated and the residue was purified by flash chromatography, elutingwith 97:3 chloroform/methanol, to provide an oil. Analysis Calc. for C₁₇H₂₅ NO₃ o1/4H₂ O: C 69.01, H 8.69, N 4.73; found: C 68.81, H 8.70, N4.58.

Example 11 N-2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!-2-hydroxyacetamide

A solution of 3-cyclopentyloxy-4-methoxyphenethylamine (0.1 g, 0.42mmol) in tetrahydrofuran (3 mL) was cooled to 0° C. and was treated withtriethylamine (0.064 mL, 0.46 mmol) and benzyloxyacetyl chloride (0.066mL, 0.42 mmol). The reaction was stirred under an argon atmosphere for0.5 h, then was partitioned between methylene chloride and acidic water.The extract was dried (potassium carbonate) and evaporated. Theresulting solid (0.16 g) was dissolved in ethanol, a small amount of 10%palladium on carbon was added, the resulting mixture was hydrogenated at50 psi for 24 h, then filtered through a pad of Celite and evaporated.Purification by flash chromatography, eluting with 5%methanol/chloroform, provided a solid: m.p. 69.5°-71° C.

Analysis Calc. for C₁₆ H₂₃ NO₄.1/8 H₂ O: C 65.01, H 7.93, N 4.74; found:C 65.03, H 7.83, N 4.83.

Example 12 N-2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!-2-methoxyacetamide

A solution of 3-cyclopentyloxy-4-methoxyphenethylamine (0.2 g, 0.85mmol) in tetrahydrofuran (6 mL) was cooled to 0° C. and was treated withtriethylamine (0.13 mL, 0.92 mmol) and methoxyacetyl chloride (0.078 mL,0.85 mmol). The reaction was stirred under an argon atmosphere for 0.25h, then was partitioned between methylene chloride and water. Theextract was dried (potassium carbonate) and evaporated. Purification byflash chromatography, eluting with 5% methanol/chloroform, provided anoil; additional 0.1 g of impure product also obtained).

Analysis Calc. for C₁₇ H₂₅ NO₄ : C 66.43, H 8.20, N 4.56; found: C66.67, H 8.18, N 4.45.

Example 13 N-2-Cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!-2-hydroxyacetamide

13a. α-Bromo-3-cyclopentyloxy-4-methoxytoluene To3-cyclopentyloxy-4-methoxybenzaldehyde (5.0 g, 22.7 mmol) was addedlithium bromide (3.94 g, 45.4 mmol) and acetonitrile (25 mL). Upondissolution, the reaction mixture was cooled to 0° C. Trimethylsilylchloride (4.32 mL, 34.0 mmol) was slowly added and the reaction mixturewas allowed to warm to room temperature and stirred for 15 min. Thereaction mixture was again cooled to 0° C. and1,1,3,3-tetramethyldisiloxane (6.68 mL, 34.0 mmol) was added dropwise.The resulting mixture was allowed to warm to room temperature. Afterstirring for 2 h, the mixture was separated into two layers. The lowerlayer was removed, diluted with methylene chloride and filtered. Thefiltrate was concentrated under reduced pressure, dissolved in methylenechloride and filtered. The solvent was removed in vacuo to provide alight tan oil, which was used without further purification.

13b. (3-Cyclopentyloxy-4-methoxyphenyl)acetonitrile To a solution ofα-bromo-3-cyclopentyloxy-4-methoxytoluene (6.6 g, 23.0 mmol) indimethylformamide (10 mL) under an argon atmosphere was added asuspension of powdered sodium cyanide (2.5 g, 51.0 mmol) indimethylformamide (40 mL). The resulting mixture was stirred at roomtemperature for 24 h, then poured into cold water (250 mL) and extractedthree times with ether/ethyl acetate. The combined organic extracts werewashed three times with water and dried (sodium sulfate). The solventwas removed in vacuo and the residue was purified by flashchromatography, eluting with 30% ethyl acetate/hexanes, to provide apale yellow oil.

13c. Methyl 2-cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)acetate. To asuspension of sodium hydride (0.69 g of an 80% suspension in mineral oilwashed three times with pentane, 22.44 mmol) in toluene (25 mL) under anargon atmosphere was added a solution of freshly distilled dimethylcarbonate (1.30 mL, 15.1 mmol) and(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (1.71 g, 7.44 mmol) intoluene (5 mL). The resulting mixture was heated at reflux for 1.25 h,with most of the solvent then removed by distillation, and the remainderwas stirred overnight at room temperature. The mixture was cooled to 0°C., partitioned between ice water and ether, and acidified. The productwas extracted with ether, the extract was dried (sodium sulfate) and thesolvent was removed in vacuo to provide an oil.

13d. 2-Cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)acetamide A solution ofmethyl 2-cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)acetate (2.1 g, 7.26mmol) in concentrated ammonium hydroxide (50 mL ) was stirred at roomtemperature for four days. A thick white precipitate formed after thefirst half hour. The reaction was cooled to 0° C., acidified to pH 2-3with 10% aqueous hydrochloric acid, extracted three times with methylenechloride/methanol and dried (magnesium sulfate). The solvent was removedin vacuo to provide an off-white solid: m.p. 160°-162° C.

13e.3-(t-Butoxycarbonylamino)-2-(3-cyclopentyloxy-4-methoxyphenyl)propioamide

To a solution of 2-cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)acetamide(0.504 g, 1.85 mmol) in methanol (25 mL) was added 70% perchloric acid(0.18 mL, 1.9 mmol) and 10% palladium on carbon (0.03 g). The resultingmixture was hydrogenated at 50 psi for 2 h and filtered through a pad ofCelite. The filtrate was concentrated in vacuo. The solid residue waspartitioned between methylene chloride and aqueous sodium carbonate andthe organic layer was dried (sodium sulfate). The solvent was removed invacuo, and the residue was dissolved in methylene chloride (25 mL) andtreated with di-t-butyldicarbonate (0.5 mL, 2.18 mmol). After 20 h, thesolvent was evaporated and the residue was purified by flashchromatography, eluting with 1:1 ethyl acetate/hexanes, to provide apale yellow solid.

13f.3-(t-Butoxycarbonylamino)-2-(3-cyclopentyloxy-4-methoxyphenyl)propionitrileA solution of3-(t-butoxycarbonylamino)-2-(3-cyclopentyloxy-4-methoxyphenyl)propioamide(0.29 g, 0.75 mmol) in dry tetrahydrofuran (5 mL) was treated withpyridine (0.135 mL, 1.66 mmol) and with trifluoroacetic anhydride (0.12mL, 0.83 mmol) dropwise. The reaction was stirred at room temperaturefor 1.5 h, then quenched with ice and partitioned between methylenechloride and water. The organic extract was dried (magnesium sulfate)and concentrated. Purification by flash chromatography, eluting with 3:7ethyl acetate/hexanes, provided an orange-yellow oil.

13g. 3-Amino-2-(3-cyclopentyloxy-4-methoxyphenyl)propionitrile Asolution of3-(t-butoxycarbonylamino)-2-(3-cyclopentyloxy-4-methoxyphenyl)propionitrile(0.26 g, 0.71 mmol) in methylene chloride (5 mL) cooled to 0° C. wastreated with the dropwise addition of trifluoroacetic acid (1.0 mL) andstirred under argon for 2 h at 0° C. and 2 h at room temperature. Thereaction was neutralized with solid sodium bicarbonate, diluted withmethylene chloride and washed with aqueous sodium bicarbonate and thenwith water. The organic extract was dried (potassium carbonate) andevaporated to provide a yellow oil.

13 h. N-2-Cyano-2-(3-cyclopentyloxy-4methoxyphenyl)ethyl!-2-acetoxyacetamide Asolution of 3-amino-2-(3-cyclopentyloxy-4-methoxyphenyl)propionitrile(0.095 g, 0.36 mmol) in methylene chloride (2 mL) was cooled to 0° C.and was treated with triethylamine (0.057 mL, 0.43 mmol) and acetoacetylchloride (0.045 mL, 0.4 mmol). The reaction was stirred under an argonatmosphere for 1.5 h, then was treated with aqueous ammonium chlorideand was extracted three times with methylene chloride. The extract wasdried (magnesium sulfate) and evaporated. Purification by flashchromatography, eluting with 1:4 ethyl acetate/methylene chloride,provided a colorless oil.

13i. N-2-Cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!-2-hydroxyacetamide Asolution of N-2-cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!-2-acetoxyacetamide(0.102 g, 0.28 mmol) in methanol (5 mL) was treated with powderedpotassium carbonate (0.096 g, 0.69 mmol) and stirred for 15 min. Themixture was diluted with water, was extracted three times with methylenechloride and the organic extract was dried (potassium carbonate) andevaporated. Purification by flash chromatography, eluting with 3%methanol/methylene chloride, provided an oil.

Analysis Calc. for C₁₇ H₂₂ N₂ O₄.1/4 H₂ O: C 63.24, H 7.02, N 8.68;found: C 63.44, H 6.85, N 8.52.

Example 14 N- 2-Cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!urea

To a solution of 2-cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine3-amino-2-(3-cyclopentyloxy-4-methoxyphenyl)propionitrile, 0.17 g, 0.66mmol! in tetrahydrofuran (5 mL) under an argon atmosphere was addedtrimethylsilyl isocyanate (0.13 mL, 0.96 mmol). The resulting mixturewas stirred overnight at room temperature. Aqueous ammonium chloride wasadded, the mixture was extracted three times with 5% methanol/methylenechloride, the extract was dried (potassium carbonate) and evaporated.Purification of the residue by flash chromatography, eluting with 4%methanol/methylene chloride, provided the urea as a white solid: m.p.55°-61° C. (sublimes).

Analysis Calc. for C₁₆ H₂₁ N₃ O₃.1/4H₂ O: C 62.42, H 7.03, N 13.65;found: C 62.35, H 6.75, N 13.54.

Example 15 N-2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!-2-aminoacetamide

15a. N-2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!-2-t-butyloxycarbonylaminoacetamideA solution of 3-cyclopentyloxy-4-methoxyphenethylamine (0.32 g, 1.37mmol) in methylene chloride (5 mL ) at room temperature under an argonatmosphere was treated with triethylamine (0.19 mL, 1.37 mmol),N,N-dimethylaminopyridine (0.17 g, 1.37 mmol) andN-t-butyloxycarbonylglycine-N-hydroxysuccinimide ester (0.37 g, 1.37mmol). The reaction was stirred for 2.5 h, then was partitioned betweenmethylene chloride and acidic water and extracted twice. The extract wasdried (potassium carbonate) and evaporated. The crude product wascombined with that of a similar reaction conducted on the phenethylamine(0.03 g, 0.13 mmol) and was purified by flash chromatography, elutingwith 5% methanol/chloroform, to provide an oil.

Analysis Calc. for C₂₁ H₃₂ N₂ O₅.1/4 H₂ O: C 63.53, H 8.25, N 7.06;found: C 63.43, H 7.89, N 7.06.

15b. N- 2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!-2-aminoacetamide Asolution of N-2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!-2-t-butyloxycarbonylaminoacetamide(0.53 g, 1.35 mmol) in methylene chloride (16 mL) cooled to 0° C. wastreated with the dropwise addition of trifluoroacetic acid (1.7 mL), wasallowed to come to room temperature and was stirred for 2.5 h. Theliquids were evaporated, the residue was partitioned between methylenechloride and saturated aqueous sodium bicarbonate and was extractedthree times. The organic extract was dried (potassium carbonate) andevaporated. Purification by flash chromatography, eluting with 5%methanol/chloroform, provided a solid: m.p. 57°-60° C.

Analysis Calc. for C₁₆ H₂₄ N₂ O₃ : C 65.73, H 8.27, N 9.58; found: C65.39, H 8.27, N 9.18.

Example 16 (4R)-N-2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!-2,2-dimethyl-1,3-dioxolane-4-carboxamide

16a. (4R)-2.2-dimethyl-1,3-dioxolane-4-carboxylic acid To a solution ofmethyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (2.21 g, 13.7 mmol)in methanol (60 mL) under an argon atmosphere was added lithiumhydroxide monohydrate (0.61 g, 14.5 mmol). After stirring at roomtemperature for 3 h, the reaction mixture was concentrated under reducedpressure. The residue was acidified with 10% HCl and extracted withmethylene chloride. The organic extract was washed with water and dried(magnesium sulfate). The solvent was removed in vacuo to provide theacid, which was used without further purification.

16b. (4R)-N-2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!-2,2-dimethyl-1,3-dioxolane-4-carboxamideTo a solution of (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (0.50g, 3.42 mmol) in 1,2-dimethoxyethane (10 mL) under an argon atmospherewas added N-methylmorpholine (0.44 mL, 3.93 mmol) and ethylchloroformate (0.38 mL, 3.93 mmol). The resulting mixture was stirred atroom temperature for 4 h, at which time was added a solution of2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (0.75 g, 3.19 mmol) in1,2-dimethoxyethane (5 mL). After stirring for 2 h at room temperature,the mixture was concentrated under reduced pressure. The residue wasdissolved in methylene chloride and washed successively with 10% HCl(twice), aqueous sodium bicarbonate and water and dried (potassiumcarbonate). The solvent was removed in vacuo and the residue waspurified by flash chromatography, eluting with 35% ethylacetate/hexanes, to provide the carboxamide as a pale yellow oil.

Analysis Calc. for C₂₀ H₂₉ NO₅.1/2 H₂ O: C 64.50, H 8.12, N 3.76; found:C 64.68, H 7.84, N 3.86.

Example 17 (2R)-N-2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!-2,3-dihydroxypropanamide

To a solution of (4R)-N-2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!-2,2-dimethyl-1,3-dioxolane-4-carboxamide(0.48 g, 1.32 mmol) in tetrahydrofuran (2.5 mL) under an argonatmosphere was added hydrochloric acid (1M, 2.5 mL) and the resultingmixture was stirred at room temperature for 5 h. Potassium carbonate wasadded, and the mixture was partitioned between methylene chloride andwater. The organic extract was washed with saturated aqueous sodiumchloride and dried (potassium carbonate). Removal of the solvent invacuo and purification of the residue by flash chromatography, elutingwith 5% methanol/methylene chloride, provided a solid (0.36 g, 85%):m.p. 58°-59° C.

Analysis Calc. for C₁₇ H₂₅ NO₅.1/10 H₂ O: C 62.79, H 7.81, N 4.31;found: C 62.63, H 7.81, N 4.71.

Example 18 (2S)-N-2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!-2,3-dihydroxypropanamide andIsobutyl N- 2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!carbamate

18a. (4S)-2,2-Dimethyl-1,3-dioxolane-4-carboxylic acid. To a solution ofmethyl (4S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (0.55 g, 3.43 mmol)in methanol (15 mL) under an argon atmosphere was added lithiumhydroxide monohydrate (0.15 g, 3.64 mmol). After stirring at roomtemperature for 2.5 h, the reaction mixture was concentrated underreduced pressure. The residue was acidified with 10% HCl and extractedwith methylene chloride. The organic extract was washed with water anddried (magnesium sulfate). The solvent was removed in vacuo to provide acolorless oil, which was used without further purification.

18b. (2S)-N-2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl!-2,3-dihydroxypropanamide andIsobutyl N- 2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!carbamate. To asolution of (4S)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (0.46 g,3.19 mmol) in 1,2-dimethoxyethane (10 mL) under an argon atmosphere wasadded N-methylmorpholine (0.41 mL, 3.67 mmol) and isobutyl chloroformate(0.48 mL, 3.67 mmol). The resulting mixture was stirred at roomtemperature for 1 h, at which time was added a solution of2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (0.75 g, 3.19 mmol) in1,2-dimethoxyethane (5 mL). After stirring for 6 h at room temperature,the mixture was concentrated under reduced pressure. The residue wasdissolved in methylene chloride and washed successively with 10% HCl,aqueous sodium bicarbonate and water and dried (potassium carbonate).The solvent was removed in vacuo and the residue was purified by flashchromatography, eluting with 3% methanol/methylene chloride to provide(2S)-N-2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!-2,3-dihydroxypropanamide:m.p. 57°-58.5° C.

Analysis Calc. for C₁₇ H₂₅ NO₅ : C 63.14, H 7.79, N 4.33; found: C62.72, H 7.60, N 4.28.

Also isolated was isobutyl N-2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl!carbamate as a white solid:m.p. 54°-55° C.

Analysis Calc. for C₁₉ H₂₉ NO₄ : C 68.03, H 8.71, N 4.18; found: C67.95, H 8.70, N 4.15.

Example 19

Formulations for pharmaceutical use incorporating compounds of thepresent invention can be prepared in various forms and with numerousexcipients. Examples of such formulations are given below.

Inhalant Formulation

A compound of formula I, (1 μg to 100 mg) is aerosolized from a metereddose inhaler to deliver the desired mount of drug per use.

    ______________________________________                                        Tablets/Ingredients      Per Tablet                                           ______________________________________                                        1.         Active ingredient 40     mg                                                   (compound of formula. I)                                           2.         Corn Starch       20     mg                                        3.         Alginic acid      20     mg                                        4.         Sodium alginate   20     mg                                        5.         Mg stearate       1.3    mg                                                                     01.3   mg                                        ______________________________________                                    

Procedure for Tablets:

Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitablemixer/blender.

Step 2 Add sufficient water portion-wise to the blend from Step 1 withcareful mixing after each addition. Such additions of water and mixinguntil the mass is of a consistency to permit its conversion to wetgranules.

Step 3 The wet mass is convened to granules by passing it through anoscillating granulator using a No. 8 mesh (2.38 mm) screen.

Step 4 The wet granules are then dried in an oven at 140° F. (60° C.)until dry.

Step 5 The dry granules are lubricated with ingredient No. 5.

Step 6 The lubricated granules are compressed on a suitable tabletpress.

Parenteral Formulation

A pharmaceutical composition for parenteral administration is preparedby dissolving an appropriate amount f a compound of formula I inpolyethylene glycol with heating. This solution is then diluted withwater for injections Ph Eur. (to 100 ml). The solution is thensterilized by filtration through a 0.22 micron membrane filter andsealed in sterile containers.

What is claimed is:
 1. A compound of formula I ##STR8## or a saltthereof, where Q is a radical of formula ##STR9## R₁ is C₇₋₁₁polycycloalkyl, C₃₋₆ cycloalkyl wherein the cycloalkyl moieties areunsubstituted or substituted by 1 to 3 methyl groups or one ethylgroup;R₂ is --CH₃ or --CH₂ CH₃ unsubstituted or substituted by 1 or morehalogens: R₃ is lower alkyl unsubstituted or substituted by one or morehalogens, --CR₄ R₅ OR₄ or --CR₄ (OR₄)CR₄ R₅ OR₄ ; R₄ and R₅ areindependently hydrogen, methyl or ethyl; R₆ is hydrogen, halogen, --C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, --CH═CR₄ R₅, cyclopropylunsubstituted or substituted by R₄, or --C.tbd.CR₄ ; R₇ is hydrogen, F,or --CH₃ unsubstituted or substituted by 1 to 3 fluoro groups; R₈ is H,F, or C₁₋₂ alkyl optionally substituted by 1 or more fluoro groups; R₉is H or unsubstituted or substituted C₁₋₆ alkyl, wherein optionalsubstituents are from one to three groups independently selected fromthe group consisting of --CH₃ or --CH₂ CH₃ unsubstituted or substitutedby 1 or more halogens; X₁ is YR₂, X₂ is O; X₃ is hydrogen, halogen or X₁; Y is O, S, SO or SO₂ ; Z is O.
 2. A composition of matter comprising acompound of formula I according to claim 1 in admixture with anexcipient.
 3. A method for treating allergic and inflammatory diseaseswhich comprises administering to a mammal in need thereof an effectiveamount of a compound of Formula I either alone or in admixture with apharmaceutically acceptable excipient.